Commercial Serological Tests for the Diagnosis of Active Pulmonary and Extrapulmonary Tuberculosis: An Updated Systematic Review and Meta-Analysis

An up-to-date systematic review and meta-analysis by Karen Steingart and colleagues confirms that commercially available serological tests do not provide an accurate diagnosis of tuberculosis. Background: Serological (antibody detection) tests for tuberculosis (TB) are widely used in developing countries. As part of a World Health Organization policy process, we performed an updated systematic review to assess the diagnostic accuracy of commercial serological tests for pulmonary and extrapulmonary TB with a focus on the relevance of these tests in low- and middle-income countries. Methods and Findings: We used methods recommended by the Cochrane Collaboration and GRADE approach for rating quality of evidence. In a previous review, we searched multiple databases for papers published from 1 January 1990 to 30 May 2006, and in this update, we add additional papers published from that period until 29 June 2010. We prespecified subgroups to address heterogeneity and summarized test performance using bivariate random effects meta-analysis. For pulmonary TB, we included 67 studies (48% from low- and middle-income countries) with 5,147 participants. For all tests, estimates were variable for sensitivity (0% to 100%) and specificity (31% to 100%). For anda-TB IgG, the only test with enough studies for meta-analysis, pooled sensitivity was 76% (95% CI 63%–87%) in smear-positive (seven studies) and 59% (95% CI 10%–96%) in smear-negative (four studies) patients; pooled specificities were 92% (95% CI 74%–98%) and 91% (95% CI 79%–96%), respectively. Compared with ELISA (pooled sensitivity 60% [95% CI 6%–65%]; pooled specificity 98% [95% CI 96%–99%]), immunochromatographic tests yielded lower pooled sensitivity (53%, 95% CI 42%–64%) and comparable pooled specificity (98%, 95% CI 94%–99%). For extrapulmonary TB, we included 25 studies (40% from low- and middle-income countries) with 1,809 participants. For all tests, estimates were variable for sensitivity (0% to 100%) and specificity (59% to 100%). Overall, quality of evidence was graded very low for studies of pulmonary and extrapulmonary TB. Conclusions: Despite expansion of the literature since 2006, commercial serological tests continue to produce inconsistent and imprecise estimates of sensitivity and specificity. Quality of evidence remains very low. These data informed a recently published World Health Organization policy statement against serological tests. : Please see later in the article for the Editors' Summary Background: Every year nearly 10 million people develop tuberculosis—a contagious bacterial infection—and about two million people die from the disease. Mycobacterium tuberculosis, the bacterium that causes tuberculosis, is spread in airborne droplets when people with the disease cough or sneeze. It usually infects the lungs (pulmonary tuberculosis) but can also infect the lymph nodes, bones, and other tissues (extrapulmonary tuberculosis). The characteristic symptoms of tuberculosis are a persistent cough, weight loss, and night sweats. Diagnostic tests for the disease include microscopic examination of sputum (mucus brought up from the lungs by coughing) for M. tuberculosis bacilli, chest radiography, mycobacterial culture (in which bacteriologists try to grow M. tuberculosis from sputum or tissue samples), and nucleic acid amplification tests (which detect the bacterium's genome in patient samples). Tuberculosis can usually be cured by taking several powerful drugs daily or several times a week for at least six months. Why Was This Study Done?: Although efforts to control tuberculosis have advanced over the past decade, missed tuberculosis diagnoses and mismanaged tuberculosis continue to fuel the global epidemic. A missed diagnosis may lead to more severe illness and death, especially for people infected with both tuberculosis and HIV. Also, a missed diagnosis means that an untreated individual with pulmonary tuberculosis may remain infectious for longer, continuing to spread tuberculosis within the community Missed diagnoses are a particular problem in resource-limited countries where sputum microscopy and chest radiography often perform poorly and other diagnostic tests are too expensive and complex for routine use. Serological tests, which detect antibodies against M. tuberculosis in the blood (antibodies are proteins made by the immune system in response to infections), might provide a way to diagnose tuberculosis in resource-limited countries. Indeed, many serological tests for tuberculosis diagnosis are on sale in developing countries. However, because of doubts about the accuracy of these commercial tests, they are not recommended for use in routine practice. In this systematic review and meta-analysis, the researchers assess the diagnostic accuracy of commercial serological tests for pulmonary and extrapulmonary tuberculosis. A systematic review uses predefined criteria to identify all the research on a given topic; meta-analysis is a statistical method that combines the results of several studies. What Did the Researchers Do and Find?: The researchers searched the literature for studies that evaluated serological tests for active tuberculosis published between 1990 and 2010. They used data from these studies to calculate each test's sensitivity (the proportion of patients with a positive serological test among patients with tuberculosis confirmed by a reference method; a high sensitivity indicates that the test detects most patients with tuberculosis) and specificity (the proportion of patients with a negative serological result among people without tuberculosis; a high specificity means the test gives few false-positive diagnoses). They also assessed the methodological quality of each study and rated the overall quality of the evidence. The researchers found 67 studies (half from low/middle-income countries) that evaluated serological tests for the diagnosis of pulmonary tuberculosis. The sensitivity of these tests varied between studies, ranging from 0% to 100%; their specificities ranged from 31% to 100%. For the anda-TB IgG test—the only test with sufficient studies for a meta-analysis—the pooled sensitivity from the relevant studies was 76% in smear-positive patients and 59% in smear-negative patients. The pooled specificities were 92% and 91%, respectively. The researchers found 25 studies (40% from low/middle-income countries) that evaluated serological tests for the diagnosis of extrapulmonary tuberculosis. Again, sensitivities and specificities for each test varied greatly between studies, ranging from 0% to 100% and 59% to 100%, respectively. Overall, for both pulmonary and extrapulmonary tuberculosis, the quality of evidence from the studies of the serological tests was graded very low. What Do These Findings Mean?: This systematic review, which updates an analysis published in 2007, indicates that commercial serological tests do not provide an accurate diagnosis of tuberculosis. This finding confirms previous systematic reviews of the evidence, despite a recent expansion in the relevant literature. Moreover, the researchers' analysis indicates that the overall quality of the body of evidence on these tests remains poor. Many of the identified studies used unsatisfactory patient selection methods, for example. Clearly, there is a need for continued and improved research on existing serological tests and for research into new approaches to the serological diagnosis of tuberculosis. For now, though, based on these findings, cost-effectiveness data, and expert opinion, the World Health Organization has issued a recommendation against the use of currently available serological tests for the diagnosis of tuberculosis, while stressing the importance of continued research on these and other tests that could provide quick and accurate diagnosis of TB. Additional Information: Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001062.